AMP-activated protein kinase inhibits K(v)1.5 channel currents of pulmonary arterial myocytes in response to hypoxia and inhibition of mitochondrial oxidative phosphorylation

作者：Moral Sanz Javier; Mahmoud Amira D; Ross Fiona A; Eldstrom Jodene; Fedida David; Hardie D Grahame; Evans A Mark

来源：The Journal of Physiology, 2016, 594(17): 4901-4915.

DOI：10.1113/JP272032

Progression of hypoxic pulmonary hypertension is thought to be due, in part, to suppression of voltage-gated potassium channels (K-v) in pulmonary arterial smooth muscle cells that is mediated by the inhibition of mitochondrial oxidative phosphorylation. We sought to determine the role in this process of the AMP-activated protein kinase (AMPK), which is intimately coupled to mitochondrial function due to its activation by LKB1-dependent phosphorylation in response to increases in the cellular AMP: ATP and/or ADP: ATP ratios. Inhibition of complex I of themitochondrial electron transport chain using phenformin activated AMPK and inhibited K-v currents in pulmonary arterial myocytes, consistent with previously reported effects of mitochondrial inhibitors. Myocyte K-v currents were also markedly inhibited upon AMPK activation by A769662, 5-aminoimidazole-4-carboxamide riboside and C13 and by intracellular dialysis from a patch-pipette of activated (thiophosphorylated) recombinant AMPK heterotrimers (alpha 2 beta 2.1 or alpha 1 beta 1 gamma 1). Hypoxia and inhibitors of mitochondrial oxidative phosphorylation reduced AMPK-sensitive K+ currents, which were also blocked by the selective K(v)1.5 channel inhibitor diphenyl phosphine oxide-1 but unaffected by the presence of the BKCa channel blocker paxilline. Moreover, recombinant human K(v)1.5 channels were phosphorylated by AMPK in cell-free assays, and K+ currents carried by K(v)1.5 stably expressed in HEK 293 cells were inhibited by intracellular dialysis of AMPK heterotrimers and by A769662, the effects of which were blocked by compound C. We conclude that AMPK mediates K-v channel inhibition by hypoxia in pulmonary arterial myocytes, at least in part, through phosphorylation of K(v)1.5 and/or an associated protein.

• 出版日期2016-9-1